Asymmetric α-allylic allenylation of β-ketocarbonyls and aldehydes by synergistic Pd/chiral primary amine catalysis

We herein describe an asymmetric α-allylic allenylation of β-ketocarbonyls and aldehydes with 1,3-enynes. A synergistic chiral primary amine/Pd catalyst was identified to facilitate the utilization of 1,3-enynes as atom-economic and achiral allene precursors. The synergistic catalysis enables the construction of all-carbon quaternary centers-tethered allenes bearing non-adjacent 1,3-axial central stereogenic centers in high level of diastereo- and enantio-selectivity. By switching the configurations of ligands and aminocatalysts, diastereodivergence can be achieved and any of the four diastereoisomers can be accessed in high diastereo- and enantio- selectivity.

Previously, we have shown metal-hydride (M-H) cycle could work in concert with chiral primary aminocatalysis to facilitate enantioselective alkylation with allene, 1,3-dienes and alkynes [25][26][27][28][29][30] . In this work, we report synergistic Pd/chiral primary amine catalysis for α-allylic allenylation of β-ketocarbonyls and aldehydes with the most atomeconomic and achiral allene precursors, 1,3-enynes (Fig. 1II). Distinctive from the dual metal synergistic catalysis, the current organo-metal dual catalytic system eliminates the necessity on coordinating groups, and thus significantly expands the scopes to include versatile β-ketocarbonyls and aldehydes for the first time. The reaction also features the construction of all-carbon quaternary centers-tethered allenes bearing a non-adjacent 1,3-axial-central chirality, a challenging target that has not been achieved before.

Reaction optimizations
Based on our preliminary successes on achiral Pd/chiral primary amine catalysis [25][26][27][28][29][30] , conjugated enyne 1a and racemic tert-butyl 2-methyl-3oxobutanoate 2a were selected as the model substrates to examine the feasibility of this design in the presence of chiral primary-tertiary (S)-A1 amine catalyst, Pd 2 (dba) 3 and DPEphos in the DCE at 40°C (Table 1). A set of chiral primary-tertiary diamine catalysts were first examined, and A1 was found to provide 3a with 90% ee, although the yield was only 51% (entry 2). Other bulkier catalysts such as A2 slightly increased the enantioselectivity but with compromised activity (entry 3 vs entry 2). A survey of classic biphosphine ligands revealed that both of the reactivity and stereoselectivity were significantly influenced by the dihedral angle of the ligand backbone. Chiral ligand L4 with the smallest dihedral angle was identified as an efficient ligand in terms of both reactivity and stereoselectivity (entries 4-6), whereas the more sterically hindered ligand L5 gave the desired adduct with >99% ee, albeit with only trace product. Ligands L6 and L7, which were effective in other metal-hydride (M-H) mediated reactions [31][32][33] , turned out to be   inactive in our Pd/aminocatalytic system (entries 10 and 11). Matchmismatch effect was noted on the ligand configuration. The use of (R)-L4/(S)-A1 led to a reversed diastereoselectivity, with unfortunately reduced activity and enantioselectivity (entry 6 vs entry 7). In addition, (race)-L4/(S)-A1 showed only slightly diminished stereoselectivity, suggesting that the chirality of ligand has only marginal effect on enantioselectivity and that aminocatalyst plays a major role in stereocontrol ( With the optimized conditions in hand, we explored the scopes of enynes by carrying out reactions with 2a, and the results are summarized in Fig. 2. A diverse array of electron-withdrawing and electrondonating groups at varying positions on the aryl units were found to be well tolerated to afford the allene products (Fig. 2, 3a-o) in 51-84% yield with excellent stereoselectivities (13:1 to >20:1 dr and exclusively >99% ee). Particularly, the enyne 1i with bromo-substitution gave the expected product 3i in 63% yield with 13:1 dr and >99% ee without obvious side products associated with the bromo-substitution in the presence of Pd. Multi-substituted arenes were also suitable as well to deliver the corresponding products in good yields with good diastereoselectivities and excellent enantioselectivities (Fig. 2, 3o, p). Heteroaryl enynes including those highly conjugate arenes were compatible with this process, providing the allene products (Fig. 2, 3q-s) in 57-76% yield with 9:1 to >20:1 dr and up to >99% ee. In addition,   alkyl-substituted enyne also showed moderate coupling reactivity with >20:1 dr and >99% ee (Fig. 2, 3t).
The practicality of this method was examined in the latestage allenylation of structurally complexed substrates bearing diverse biologically active molecules. For example, the reactions worked smoothly with enynes tethered to drugs such as Naproxen (3aa), (1S)-(-)-Camphanic acid (3bb), Febuxostat (3cc) and Cholesterol (3dd), to give the desired adducts with moderate reactivity and high diastereo-and enantioselectivities (Fig. 2).     We also examined the scope of β-ketocarbonyls. As show in Fig. 3A, different ester groups with varied sizes were generally tolerated to give the desired products in good yields and excellent stereoselectivities (Fig. 3A, 4a-d). Large α-substituent led to reduced reactivity and stereoselectivity (Fig. 3A, 4f), while small one worked well to give the desired adduct (Fig. 3A, 4e) in 11:1 dr, >99% ee and 64% yield. The reaction with cyclic β-ketoesters such as cyclopentanone and cyclohexanone worked well to deliver the corresponding products with excellent stereoselectivities but in lower yields (Fig. 3A and 4g-i), most likely due to the lower reactivity of these ketones.
We then explored the reactions with α-branched aldehydes (Fig. 3C), for which there has been no examples on asymmetric allylic allenylation. α-Arylpropanals can be well applied and the reactions proceeded smoothly to give the desired adducts with good yields and high stereoselectivity (Fig. 3C, 4q-t). The diastereoselectivity was relatively lower comparing with that of the reactions with βketocarbonyls.
The reaction between 1l and 2a could be conducted at a gram scale with comparable results (Fig. 2, 3l), demonstrating the practicality of the current reaction. In addition, this series of products are rich in functionality for further transformations that were enormously demonstrated [48][49][50][51][52] . In our cases, the initially obtained allylic allene adducts could be easily transformed in order to determine the stereochemical configurations. Upon treatment of 3a with 2, 4-dinitrophenylhydrazine followed by HCl (1 M, 1.0 equiv.) in MeOH led to compound 5a in 67% yield and 19: 1 dr with 99% ee (Fig. 5, 5a). Reduction of the keto moiety of (S,S)-3a over NaBH 4 gave 5b in 98% yield (Fig. 5, 5b). The absolute configuration of reduction product 5b was assigned based on crystallographic analysis.

Proposed catalytic cycle
In accordance with previous studies 23, [25][26][27][28][29][30] , a synergistic Pd/aminocatalytic cycle could be proposed as described in Fig. 6. For palladium catalysis, a L*/Pd-H complex generated in situ underwent hydrocarbonation with enyne regioselectively to give the intermediate I, which could interconvert rapidly to the key π-allyl-palladium syn-η 3 -int II via σ-π rearrangement 15,53,54 . The protonated aminocatalyst may serve as the proton source for Pd-H formation. Subsequently, intermediate syn-η 3 -Int II coupled with the enamine intermediate III to give the desired product 3a after hydrolysis. On the basis of experimental observations as well as our previous studies 27 , a steric model could be proposed to account for the observed stereoselectivity regarding the chiral center construction (Fig. 6, III), whereas chiral ligand in synergy with aminocatalysts plays the key role in steering the axial selectivity.
In summary, we have developed a synergistic chiral primary amine/Pd catalysis for α-allylic allenylation of ketones and aldehydes. The catalysis enables the use of 1,3-enynes as the atomeconomic and achiral allene precursors, and features high

Aminocatalysis
Palladium Catalysis stereoselectivity in the construction of non-adjacent 1,3-axial central chirality bearing all-carbon quaternary centers. This method could be generally applied to β-ketocarbonyls and aldehydes to afford the allenylation products with high enantioselectivity and diastereoselectivity. Divergence on the stereoselectivity could be achieved by varying the configurations of chiral primary amine and chiral ligands.

Data availability
All data are available from the authors upon request. Supplementary information and chemical compound information are available along with the online version of the paper. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition number 2222345 (5b). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ structures.